PROJECT SUMMARY/ABSTRACT: Drug abuse and addiction are significant problems with estimated annual costs in excess of $600 billion. The mesocorticolimbic dopamine system, which is comprised of dopamine neurons in the ventral tegmental area (VTA) and their afferent and efferent projections, is the principal neural circuit controlling motivation and reward-related behavior including drug intake, and changes in dopamine circuits have been widely shown to play an important role in drug abuse and the transition to addiction. Addictive drugs increase dopamine release and produce plastic changes in the strength of neural connections within dopamine circuits that are thought to play an important role in the development of addiction. A critical barrier to progress in combating drug abuse and addiction is our limited understanding of how dopamine neuron activity is controlled and how drugs cause plasticity within dopamine circuits. This includes our limited understanding of the function and regulation of excitatory afferent inputs to VTA dopamine neurons, which arise from multiple distinct brain regions and play an essential role in controlling dopamine neuron activity. A key gap in our current knowledge of the regulation of VTA dopamine neuron activity is that it is unknown whether the excitatory afferent inputs to VTA dopamine neurons that originate from distinct locations differ in either their function or their ability to regulate dopamine neurons. For example, it is unclear whether excitatory inputs arising from individual brain regions preferentially or exclusively synapse on dopamine neurons projecting to specific efferent targets, and there has been little study of whether the inputs from different regions vary in their baseline intrinsic characteristics or their ability to influence dopamine neuron activity. In addition, it is unknown whether drugs strengthen all excitatory inputs equally or if only inputs from specific brain regions are strengthened by drugs. The goal of this project is to advance our knowledge of how excitatory afferent inputs control VTA dopamine neuron activity and how drugs alter dopamine neuron activity to cause addiction so new strategies can be identified to combat drug abuse and addiction. We will use optogenetic and electrophysiological approaches to test the central hypothesis that excitatory afferent inputs to VTA dopamine neurons arising from individual brain regions differ in their baseline strength, intrinsic characteristics and their ability to undergo drug induced plasticity. These studies will impact the drug addiction field by significantly advancing our understanding of the regulation of the mesocorticolimbic dopamine system and how it is altered by abused drugs. Ultimately this information may aid in the identification of new strategies that can be used to combat drug abuse and addiction.